MICROGLIAL ADP RECEPTORS IN ALZHEIMER’S DISEASE: THERAPEUTIC POTENTIAL AND IMPLICATIONS

Microglial cells play a key role in maintaining brain homeostasis, contributing to synaptic plasticity and modulating neuronal activity through their interactions with neurons. Disruptions in microglia-neuron communication have been implicated in neurodegenerative disorders, including Alzheimer’s disease (AD). This study aimed to investigate the role of microglial ADP receptors -activated by nucleotides released from distressed neurons- in AD pathogenesis, with a focus on their effects on neuronal activity and disease progression. To assess the contribution of microglial ADP receptor signalling to AD progression, we used a novel APP/Tau transgenic mouse model of AD pathology. Mice at early and advanced disease stages were chronically treated with a pharmacological modulator of the ADP receptor, and cognitive and motor functions were evaluated. In parallel, biochemical and histological analyses were performed to examine changes in protein markers associated with neurodegeneration and neuroinflammation following treatment. Chronic modulation of ADP receptor-mediated signalling resulted in moderate improvements in spatial memory and motor coordination in APP/Tau mice. Moreover, biochemical and histological analyses revealed significant alterations in the expression of microglial, neuronal, astrocytic, synaptic and inflammatory markers linked to AD pathology, with several of these changes being partially attenuated by treatment. Together, these findings indicate that microglial signalling pathways associated with ADP receptors contribute to AD pathogenesis and that their pharmacological modulation can partially restore both functional and molecular deficits in APP/Tau mice. Targeting microglial ADP receptors may therefore represent a potential therapeutic strategy for AD, although further studies are required to clarify the underlying mechanisms and therapeutic efficacy.